Scientists finally reveal what’s behind long COVID’s mysterious brain fog

Despite its widespread impact, the biological roots of Long COVID and brain fog have remained unclear. Earlier brain imaging studies revealed some structural alterations, but they failed to identify the molecular disturbances responsible for cognitive decline. Because it is difficult to directly observe the molecules that facilitate communication between brain cells, researchers have lacked reliable biomarkers to diagnose Long COVID or develop targeted treatments.

To shed light on this mystery, a research group led by Professor Takuya Takahashi at the Graduate School of Medicine, Yokohama City University (Japan), achieved a major breakthrough in understanding the molecular basis of Long COVID brain fog. In a study published on October 1, 2025, in Brain Communications, the team proposed that people experiencing brain fog may show disrupted activity of AMPA receptors (AMPARs), which are essential for learning and memory. This idea stemmed from prior studies linking AMPAR dysfunction to psychiatric and neurological disorders such as depression, bipolar disorder, schizophrenia, and dementia. The researchers employed a newly developed technique, [11C]K-2 AMPAR PET imaging, to directly measure and visualize the density of these receptors in the living human brain.

When comparing 30 individuals with Long COVID to 80 healthy volunteers, the scientists discovered a striking and widespread increase in AMPAR density throughout the brains of affected patients. The degree of this increase closely matched the severity of cognitive symptoms, establishing a strong molecular link between receptor changes and brain fog. They also found that higher levels of inflammatory markers were associated with elevated AMPAR density, suggesting that inflammation may play a role in altering receptor expression.

Overall, the study provides compelling biological evidence connecting Long COVID to measurable brain changes. The observed AMPAR overactivity may help explain cognitive symptoms and points to potential treatment targets. Medications designed to moderate AMPAR function could, in theory, help reduce brain fog. The team also demonstrated that their imaging approach could distinguish Long COVID patients from healthy individuals with 100% sensitivity and 91% specificity. "By applying our newly developed AMPA receptor PET imaging technology, we aim to provide a novel perspective and innovative solutions to the pressing medical challenge that is Long COVID," says Prof. Takahashi.

While more research is needed before an effective treatment can be developed, these results mark a significant advancement in understanding the disorder. "Our findings clearly demonstrate that Long COVID brain fog should be recognized as a legitimate clinical condition. This could encourage the healthcare industry to accelerate the development of diagnostic and therapeutic approaches for this disorder," concludes Prof. Takahashi.

In conclusion, this groundbreaking study offers the first clear molecular explanation for Long COVID-related brain fog and opens the door to new diagnostic tools and treatment options that could greatly benefit affected patients.

Funding information

This clinical trial project received donations through the READYFOR crowdfunding platform. Additional support came from the Takeda Science Foundation (T.T.), the Japan Agency for Medical Research and Development (AMED) under grant numbers JP24wm0625304 (T.T.), and the JST Establishment of University Fellowships Toward the Creation of Science Technology Innovation program under grant JPMJFS2140 (Y.F.).